Influenza infection (also referred to as “influenza” or “the flu”) is a highly contagious disease with the potential to be devastating both in developing and developed countries. Influenza rapidly spreads in seasonal epidemics affecting 5-15% of the population and the burden on health care costs and lost productivity are extensive (World Healthcare Organization (WHO)).
There are three genera of influenza virus (types A, B and C) responsible for infectious pathologies in humans and animals. The type A and type B viruses are the agents responsible for the influenza seasonal epidemics (type A and B) and pandemics (type A) observed in humans.
Influenza A viruses can be classified into influenza virus subtypes based on variations in antigenic regions of two genes that encode the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) which are required for viral attachment and cellular release, respectively. Currently, sixteen subtypes of HA (H1-H16) and nine NA (N1-N9) antigenic variants are known in influenza A virus. Only some of the influenza A subtypes (i.e. H1N1, H1N2 and H3N2) circulate among people, but all combinations of the 16 HA and 9 NA subtypes have been identified in animals, in particular in avian species. Animals infected with influenza A often act as a reservoir for the influenza viruses and certain subtypes have been shown to cross the species barrier to humans, such as the highly pathogenic influenza A strain H5N1.
To date, less attention has been paid to influenza B viruses. This may be due to the fact that—primarily being restricted to humans as host—influenza B viruses lack the large animal reservoirs that are key to the emergence of pandemic influenza A strains. However, the cumulative impact of annual epidemics during interpandemic periods exceeds that of pandemics and although the morbidity and mortality rates attributable to influenza B are lower than those of e.g. H3N2 viruses, they are higher than those of H1N1 viruses (Thompson et al., JAMA 289(2): 179-186 (2003), Thompson et al., JAMA 292(11): 1333-1340 (2004)).
The evolution of influenza B viruses is characterized by co-circulation of antigenically and genetically distinct lineages for extended periods of time. The influenza B/Lee/40 strain was the first influenza B virus that has been identified (Krystal et al., Proc. Natl Acad. Sci. 79(15):4800-4804 (1982)). Two lineages, represented by the prototype viruses B/Victoria/2/87 (Victoria lineage) and B/Yamagata/16/88 (Yamagata lineage), are currently distinguished (Kanegae et al., J. Virol. 64(6): 2860-2865 (1990), Rota et al., Virology 175(1): 59-68 (1990)). B/Yamagata was the major lineage circulating until the 1980s, when B/Victoria lineage viruses appeared. Since then, drift variants of both influenza B lineages have been co-circulating globally, with both lineages concurrently circulating in recent influenza seasons.
Current approaches to dealing with annual influenza epidemics include annual vaccination. However, because circulating influenza viruses in humans are subject to frequent antigenic changes, annual adaptation of the influenza vaccine formulation is required to ensure the closest possible match between the influenza vaccine strains and the circulating influenza strains. In addition, antiviral drugs, such as oseltamivir (Tamiflu®) are used for prevention and treatment of influenza infection. The number of influenza virus strains showing resistance against antiviral drugs, such as oseltamivir is, however, increasing.
An alternative approach is the development of antibody-based prophylactic or therapeutic treatments to neutralize various seasonal and pandemic influenza viruses. Thus, several hemagglutinin-specific antibodies capable of neutralizing influenza A and/or B viruses have been described (e.g. WO2008/028946, WO2013/007770, WO2013/132007). Monoclonal antibodies cross-reactive with hemagglutinin of influenza viruses from both influenza B lineages have furthermore been described to date (Dreyfus et al., Science 337:1343-1348 (2012), Kubota-Koketsu et al., Biochem. Biophys. Res. Commun 387(1):180-185 (2009), Wrammert et al., Nature 453(7195):667-671 (2008)).
Given the fact that influenza B viruses are the major cause of seasonal influenza epidemics every 2-4 years, and in view of the severity of the respiratory illness caused by certain influenza B viruses, as well has the high economic impact of the seasonal epidemics, there is an ongoing need for effective means for the prevention and treatment of influenza caused by influenza B subtypes. There is thus a need for binding molecules, preferably broadly neutralizing human binding molecules, capable of cross-neutralizing influenza B viruses.